EP1373433A1 - Cubic liquid crystalline phase precursor - Google Patents
Cubic liquid crystalline phase precursorInfo
- Publication number
- EP1373433A1 EP1373433A1 EP02707815A EP02707815A EP1373433A1 EP 1373433 A1 EP1373433 A1 EP 1373433A1 EP 02707815 A EP02707815 A EP 02707815A EP 02707815 A EP02707815 A EP 02707815A EP 1373433 A1 EP1373433 A1 EP 1373433A1
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- EP
- European Patent Office
- Prior art keywords
- cubic
- precursor
- phase
- liquid crystalline
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K19/00—Liquid crystal materials
- C09K19/52—Liquid crystal materials characterised by components which are not liquid crystals, e.g. additives with special physical aspect: solvents, solid particles
- C09K19/54—Additives having no specific mesophase characterised by their chemical composition
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K19/00—Liquid crystal materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K19/00—Liquid crystal materials
- C09K19/52—Liquid crystal materials characterised by components which are not liquid crystals, e.g. additives with special physical aspect: solvents, solid particles
- C09K2019/528—Surfactants
Definitions
- This invention relates to functionalized cubic liquid crystalline phases and methods for their preparation and use. More specifically, this invention relates to functionalized cubic liquid crystalline phase materials that have properties tailored to specific uses.
- bicontinuous cubic phase liquid crystals are composed of mixtures of lipid and water arranged into bilayers.
- the bilayers are twisted into a periodic, three-dimension structure that minimizes the energy associated with bending the bilayers (i.e. minimize curvature energy).
- These structures are 'honeycombed' with bicontinuous domains of water and lipid that is reminiscent of an organic zeolite or highly-structured microemulsion.
- the structure can simultaneously accommodate water-soluble, lipid-soluble and amphiphilic molecules and provide pathways for diffusion of water-soluble and lipid-soluble materials.
- P n3m D-surface
- I a3d G-surface
- I m3m P-surface
- phase behavior of a broad range of monoglycerides has been documented and modifications to the phase behavior have been defined. See Qiu, H., Caffrey, M., "The phase diagram of the monoolein/water system: metastability and equilibrium aspects", Biomaterials, 1999, 21(3), 223-234. Accordingly, monoolein-based bicontinuous cubic liquid crystal phase have good temperature stability, high internal surface area, gel-like viscosity, relative insensitivity to salt and solvent compositions, and use low cost raw materials which make them practical for commercial applications. Monoolein naturally exhibits P n3m and I a3d , with I m3m present with the addition of proteins.
- Cubic phase liquid crystals have been used in gel, dispersion and precursor form. 'Gels' are mixtures that contain a majority of the cubic phase liquid crystal. It is common for either mixture to exclusively contain cubic liquid crystal phase. Applications for these gels can range from drug delivery vehicles (See Shah, J. C, Sadhale, Y., Chilukuri, D. M., Adv. Drug Delivery Rev., 2001, 47(2-3), 229-250), to a matrix in which membrane proteins can be crystallized (See Landau, E., Rosenbusch, J., Proc. Natl. Acad. Sci.
- compositions of bio-adhesive liquid crystal gels including the cubic phase liquid crystals and precursors.
- Compostions include an active, a cubic phase forming lipid, and a structurant that is added without changing the ⁇ structure of the liquid crystal. These compositions do not disclose the use of hydrotropes to form liquid crystals.
- Engstrom et al., US 5,753,259 discloses a composition and method of use of liquid crystal gels, including cubic phase liquid crystals, for controlled release applications.
- the disclosed gels are fabricated from a mixture of lipid, solvent, and bioactive materials including nucleic acids.
- these gel compositions do not utilize hydrotropes.
- 'Dispersions' are particles of cubic liquid crystalline phase material that are often submicron in size. Particles are generally dispersed in a liquid medium and are often termed Cubosomes. Cavitating a mixture of lipid and liquid generally makes dispersions of cubic phase liquid crystals. This requires high pressures and numerous passes before homogeneous nanoparticle dispersions are produced (See Ljusberg-Wahren, H, Nyberg, L., Larsson, K., Chimica Oggi, 1996, 14, 40-43). Cubosomes have distinct practical advantages over vesicles and liposomes because cubosomes are an equilibrium phase (See Laughlin, R. G. Colloids and Surfaces A, 1997, 128, 27-38).
- Cubosomes also possess much greater internal surface area than vesicles or liposomes and are more resilient against degradation.
- Anderson, WO 99/12640, and Landh et al., US 5,531,925 disclose cubic phase compositions and preparations for delivery and uptake of active agents.
- the particles comprise a center containing liquid crystalline or liquid material and an exterior of solid particulate.
- the composition of the liquids comprise a lipid and polar solvent without the sue of hydrotropes.
- 'Precursors' are mixtures that are not cubic phase liquid crystals but form cubic phase liquid crystals as a consequence of a stimulus.
- Precursors can be used to dispense a mixture in a form that readily flows, but spontaneously converts to a more viscous liquid crystal with the stimulus at a target location. This is applicable to treatments for periodontal disease (See Norling, Tomas, Lading, Pia, Engstroem, Sven, Larsson, Kare, Krog, Niels, Nissen, Soeren Soe, J. Clin. Periodontol, 1992, 19(9, Pt. 2), 687-92.
- Larson et al., US 5,196,201 discloses the preparation and composition of precursors used as implants to treat aliments such as the repair of bone tissue. These precursors are composed of a water-based liquid, lipid, and optionally a triglyceride mixed to form a more concentrated L2 or D phase, which flows more readily, and converts to cubic phase upon the addition of water.
- Leng et al., US 5,593,663 discloses combinations and preparations of antiperspirant, which uptake sweat upon application to form a viscous liquid crystalline phase, including cubic phase. However, neither of these materials contains functionalization materials.
- Cubic liquid crystalline phase materials are limited in use due to restriction of their natural, or unmodified, properties.
- the natural properties of cubic phases limit the ability to solubilize active ingredients.
- broad classes of actives do not effectively load (or subsequently release) because the cubic phase lacks specific interaction with the loaded active. If the active is modified to effectively load in the cubic phase, it may lose its effectiveness.
- FIG. 1 is a phase diagram representing the behavior of composition containing a hydrotrope, a combination of amphiphile and additive, and a solvent.
- FIG. 2 represents a ketoprofen molecule in a functionalized cubic phase bilayer.
- This invention relates to precursors, bulk cubic liquid crystalline gels, dispersions of cubic liquid crystalline gel particles, cubic liquid crystalline gel particles, and combinations thereof. All percentages, ratios, and proportions used herein are by weight unless otherwise specified. All measurements are made at 25°C, unless otherwise specified. All U.S. Patents and printed publications cited are herein incorporated by reference.
- Amphiphile means a molecule with both hydrophilic and hydrophobic (lipophilic) groups (e.g, surfactants, lipids, and polymers).
- “Anchor” means a small molecule, including surfactants that have a lipid-soluble 'tail' with a water-soluble 'head'. Without wishing to be bound by theory, it is thought that the role of the lipid-soluble tail is to dissolve into the bilayers of the cubic phase, and the role of the water-soluble head might be to provide a specific (or tailored) interaction such as an electrostatic or hydrogen bond with the materials of interest.
- Body cubic gel means a viscous, structurally isotropic gel (clear, translucent, or opaque) having a normal, or reversed, cubic liquid crystalline structure, with a composition matching a cubic liquid crystalline region of a phase diagram representing the phase behavior of ingredients in the composition.
- Bulk cubic gel is also referred to herein as bulk cubic liquid crystalline gel.
- Colloidally stable means that when cubic gel particles are dispersed in a solvent, the particles do not coalesce, flocculate, or agglomerate over some reasonable time.
- Cubic gel particles means the dispersed form of bulk cubic gel; technically they are cubic liquid crystalline gel in equilibrium with either the solvent, isotropic liquid phase, lamellar phase, or a combination of two of these. Cubic gel particles are also referred to herein as cubic liquid crystalline gel particles.
- “Cubic liquid crystalline phase material” means a composition that falls within a cubic liquid crystalline phase region on a phase diagram for the ingredients in the composition or a composition that falls within a region on the phase diagram where cubic liquid crystalline phase is in equilibrium with another phase.
- Cubic liquid crystalline phase material includes bulk cubic gels, cubic gel particles, and dispersions of cubic gel particles.
- Cuboplex means a functionalized cubic liquid crystalline phase material according to this invention.
- Gel means a Theologically semisolid system.
- Gel includes cubic liquid crystalline materials such as bulk cubic gels and dispersions of cubic gel particles.
- Hydrotroprope means a surfactant-type molecule (comprising at least one hydrophilic group and at least one hydrophobic group), wherein the molecule has too short or too soluble a hydrophobic group or too insoluble or too large a hydrophilic group to display surfactant phase behavior.
- Hydrotropes are highly soluble in water and do not form aggregates in solution (e.g., micelles). Hydrotropes dissolve amphiphiles.
- Hydrotropes do not prevent formation of a cubic liquid crystalline phase upon dilution of a mixture of the hydrotrope and amphiphile with a solvent.
- the hydrotropes enhance the miscibility of weakly polar and otherwise water-insoluble molecules (such as monoolein) with aqueous solutions; this effect is commonly known as "salting-in”.
- the hydrotrope is typically present in a substantial concentration (i.e., 1% or more) to display the hydrotropic properties described above. "Ll” means a dilute liquid phase.
- L2 means a concentrated liquid phase
- Lipid means any amphiphilic molecule of intermediate molecular weight that contains a substantial portion of aliphatic or aromatic hydrocarbon.
- Paste means a liquid for topical application, preferably to the skin of an animal (preferably a human), whose viscosity is enhanced to the point that flow is largely inhibited by the presence of undissolved, as well as dissolved, solids.
- Precursor means a formulation that will form a cubic liquid crystalline phase material upon action by a stimulus.
- the stimulus can be the addition of some specified material such as additional hydrotrope, amphiphile, or solvent; the removal of some specified material such as a portion of the hydrotrope, amphiphile, or solvent; a temperature change; a pressure change; addition of salt; or a pH change in aqueous systems.
- Stabilizer means an agent that prevents aggregation, coalescence, and flocculation of dispersed phase particles. Stabilizers impart colloidal stability to dispersed cubic gel particles. Stabilizers include small particulates that absorb upon surfaces of the particles, ionic materials, polymers, charged lipids, surfactants, and liquid crystalline phase adsorbed to the surfaces of the particles.
- “Surfactant” means an amphiphile that exhibits the following properties in water: (1) it reduces the interfacial tension, and (2) it self-assembles in solution at low concentrations.
- Tether means a molecule larger than an anchor, including modified polymers, proteins, and enzymes that have a lipid-soluble fragment and a water-soluble fragment. Without wishing to be bound by theory, it is thought that the role of the lipid-soluble fragment is to dissolve into the bilayers of the cubic phase, and the role of the water- soluble fragment might be to provide a specific (or tailored) interaction such as an electrostatic or hydrogen bond with the materials of interest. Tethers. "Thermodynamically stable" means that a system is at its lowest energy state or a system that is kinetically trapped in the same state for some reasonable time. Precursor
- the precursor generally can comprise a hydrotrope, an amphiphile capable of forming a cubic liquid crystalline phase, an optional solvent, and an additive selected from the group consisting of anchors, tethers, and/or combinations thereof.
- the precursor can optionally comprise an active ingredient. Hydrotrope
- the hydrotrope can be a single hydrotrope or a combination of two or more hydrotropes capable of dissolving an amphiphile and allow formation of cubic gel particles dispersed in isotropic liquid phases.
- the hydrotrope does not prevent formation of a cubic liquid crystalline phase upon sufficient dilution of a mixture of the hydrotrope and amphiphile with a solvent.
- the hydrotrope can function as a process aid to dissolve an amphiphile and eliminate solids handling in processes to make precursors, gels, dispersions, and other particles of this invention.
- the hydrotrope can also prevent an additive from crystallizing and increase the amount of additive that can be added to a precursor, gel, dispersion, and/or particle.
- hydrotropes include alcohols, polyols, alcohol ethoxylates, surfactants derived from mono- and poly- saccharides, copolymers of ethylene and propylene oxide, fatty acid ethoxylates, sorbitan derivatives, sodium butyrate, nicotinamide, procaine hydrogen chloride, ethylene glycol, propylene glycol, glycerol, and polyglyceryl esters, the ethoxylated derivatives thereof, and combinations thereof.
- exemplary hydrotropes include methanol, ethanol, 1 ,4-butanediol, 1,2- hexanediol, sodium butyrate, nicotinamide, and procaine hydrogen chloride.
- a suitable hydrotrope is determined by preparation of a composition comprising the proposed hydrotrope, an amphiphile, and a solvent.
- a hydrotrope can be suitable if the composition forms a cubic phase or cubic phase in combination with another phase.
- a preferred hydrotrope composition forms a cubic phase or cubic phase in combination with an isotropic liquid.
- Polarized light microscopy PLM can be used to determine whether the composition formed cubic phase. PLM can be carried out on a polarized light microscope or constructed light box, as described by Laughlin, R.G., J. Colloid Interface Sci, 55, 239-242 (1976). Ll, L2, L3, and cubic phases show no birefringence and appear dark.
- Cubic phases are very viscous while the other phases (i.e., Ll, L2, and L3) are less viscous, like water. Therefore, it is believed that a lack of birefringence in combination with bulk, solid-like rheological properties indicates the presence of cubic phase. Amphiphile
- amphiphile can be a single amphiphile or a combination (e.g., mixture) of two or more amphiphiles capable of forming a cubic liquid crystalline phase.
- amphiphiles are surfactants capable of forming cubic liquid crystalline phases in the presence of a hydrotrope, solvent, and additive.
- Suitable hydrophilic groups and methods for the selection of suitable hydrophilic groups are disclosed in Laughlin, R.G., The Aqueous Phase Behavior of Surfactants, Academic Press, New York, 1994, pg. 255, and International Patent Publication WO 99/12640.
- suitable amphiphiles are excerpted in Tables 1-5 below.
- R' represents a hydrocarbon group, preferably an alkyl group.
- M represents a metal atom.
- the subscript m is 1, 2, or 3.
- X represents a halogen atom.
- Exemplary, but non-limiting, lipophilic groups include monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, surfactants, and siloxanes. Suitable monovalent hydrocarbon groups have 6 to 22 carbon atoms, preferably 8 to 22 carbon atoms, more preferably 10 to 18 carbon atoms. Substituted monovalent hydrocarbon group include halogenated monovalent hydrocarbon groups, typically having 6 to 22 carbon atoms. The monovalent hydrocarbon groups and substituted monovalent hydrocarbon groups can be saturated or unsaturated, branched or unbranched. Preferred branched hydrocarbon groups typically have 8 to 22 carbon atoms. Preferred linear hydrocarbon groups have 8 to 18 carbon atoms. It is preferred that an amphiphile include surfactants having HLB values of about
- Suitable monoglyceride should have sufficient purity to form cubic liquid crystalline phase in combination with solvent and the hydrotrope.
- a monoglyceride is typically greater than about 40% to 100% pure, preferably about 82.5 to 100% pure, however, a purity of less than about 40% may also be suitable.
- a class of preferred surfactants includes monoglycerides having the general formula:
- R is selected from the group consisting of monovalent hydrocarbon groups of 6 to 22 carbon atoms, preferably 8 to 22 carbon atoms, more preferably 10 to 18 carbon atoms, and monovalent halogenated hydrocarbon groups of 6 to 22 carbon atoms.
- the monovalent hydrocarbon groups can be saturated or unsaturated, branched or unbranched.
- Preferred branched hydrocarbon groups typically have 8 to 22 carbon atoms.
- Preferred linear hydrocarbon groups have 8 to 18 carbon atoms.
- Preferred monoglycerides have a melting point > 40°C.
- International Patent Publication No. WO 99/12640 discloses suitable amphiphiles that can form cubic liquid crystalline phase.
- amphiphiles are disclosed in U.S. Patent No. 5,756,108 and include 3,7, 11 , 15-tetramethyl- 1 ,2,3-hexadecanetriol, phytanetriol, N-2-alkoxycarbonyl derivatives of N-methylglucamine, and unsaturated fatty acid monoglycerides, monoglyceride surfactants such as glycerol monooleate (HLB of 3.8), glycerol monostearate (HLB 3.4), ethoxylated alcohol surfactants such as C, 2 EO 2 , C 12 EO 23 , and
- amphiphiles can include amphoteric surfactants such as betaines, glycinates, amino propionates, and combinations thereof.
- amphiphiles include lipids of biological origin such as fatty acids, acyl glycerols, glycerolphospholipids, phosphatidic acid (and salts thereof), phosphatidylethanolamine, phosphatidylcholine (lecithin), phosphatidylserine, phosphatidyllinositol, phosphatidylethanolamine, spingolipids (Ceramides), spingomyelin, cerebroside, glucocerebroside, ganglioside, steriods, cholesterol esters (stearates, etc.), sugar-based surfactants, glucolipids, galactolipids, and combinations thereof.
- lipids of biological origin such as fatty acids, acyl glycerols, glycerolphospholipids, phosphatidic acid (and salts thereof), phosphatidylethanolamine, phosphatidylcholine (lecithin), phosphatidylserine
- Solvent The solvent can be a single solvent or a combination of two or more polar or non- polar solvents and may contain other ingredients, such as buffers and/or stabilizers.
- polar solvents include water, glycerol, polyglycols such as polyethylene glycol, formamides such as formamide, n-methyl formamide and dimethylformamide, ethylammonium nitrate, and combinations thereof.
- nonpolar solvents include aliphatic hydrocarbons, such as alkanes and fatty esters such as lanolin, and substituted hydrocarbons, such as halogenated hydrocarbons. Additives
- the additive is an anchor, a tether, and/or a combination thereof having a low Krafft temperature, preferably below about 25°C to prevent crystallization.
- the anchors are selected from the group consisting of positive charged surfactants and negative charged surfactants. Examples of suitable surfactants can be found in McCutcheon, Emulsifiers & Detergents, North American Edition, vol. 1 (1994).
- Preferred positive charged surfactants include dioctyldecylamine hydrogen chloride.
- Preferred negative charged surfactants include potassium oleate.
- Tethers are preferably selected from the group consisting of derivatized polysaccharides and linear substituted polymers. However, the exact choice of anchor and/or tether depends on various factors including the intended use of the precursor, gel, dispersion, or particles incorporating said anchor and/or tether and any active ingredients that will be added.
- tethers There are at least two types of tethers.
- One type can be thought of as a large surfactant, for example,
- one end of the molecule is a lipid-soluble fragment or chain and at the other end is the added water-soluble fragment for specific functionality.
- a large polymeric spacer or backbone can separate these groups.
- Another tether introduces a lipid-soluble fragment (e.g. aliphatic chain) that can attach to the bilayer with a water-soluble polymeric fragment that has multiple site for interaction, for example, a polydentate ligand such as:
- Lys Lysine
- PVA polyvinyl alcohol
- n is an integer from about 1 to about 50.
- Preferred tethers are linear, branched, block copolymers, random copolymers, or grafted copolymers.
- Exemplary monomers (in mono- or co-polymer applications), anchors, and tethers are tabulated in Table 6.
- surfactants containing the hydrophilic groups in Tables 3 and 4, above may be used as a tether or active when they are not being used as an amphiphile.
- the additive has a hydrophobic chain length matching the hydrophobic domain of the cubic phase to improve the effective solubility in the bilayer of the cubic phase.
- the additive can have minimal solubility in the solvent to ensure that the additive is associated with the cubic phase rather than partitioned into the solvent.
- anchors di-chain over mono-chain surfactants and lipids are preferred.
- a higher solvent solubility may be required than for a corresponding anchor due to potential multiple molecular attachment sites.
- Charged-head group surfactants, lipids, and polymers are used when desiring pH, solvent or ionic strength-triggered formulations.
- additives can be selected using rules of electrostatics and hydrogen bonding, for example, selecting an additive to have an electrostatic interaction with a target such as another active ingredient.
- a target such as another active ingredient.
- it can be generally preferable to maximize the charge on anchor or tether. This can be changed by eliminating the point charge, for example, by protonating a carboxylate.
- any dielectric constant of the medium can vary according to the need.
- the addition of salt can increase the dielectric constant of the solution, decreasing the interaction between materials. Therefore, it is believed to be preferable to get the materials as close as possible to maximize the interactions.
- presence of a hydrotrope in an additive can prevent additives from crystallizing and can allow the amount of additive to be increased or broaden the range of additives that can be used.
- the additive can be selected to hydrogen bond with a target, for example, an active ingredient.
- Ethylene oxide based head group surfactants, lipids, and polymers can be used when desiring temperature-triggered 'on-demand' formulation.
- the precursor described above may further comprise an active ingredient (active).
- active may be one active or a combination of two or more actives.
- the active can be added in amounts such that bulk cubic gel made from the precursor will contain up to about 15% of active, preferably about 1 to abut 10% of active wt/wt of gel.
- the active can be an agrochemical such as water and non-water soluble pesticides and herbicides. Pesticides and herbicides may be incorporated into the ternary system as an active ingredient with hydrotropic properties or as an active ingredient separate from the hydrotrope.
- pesticides include organophosphates such as diazinon and non-organophosphates such as diclofop-methyl, terrazole, vinclozolin, atrazine, oxamyl propargite, and triallate.
- Exemplary, and non-limiting, herbicides include atrazine, nicosulfuron, carfentrazone, imazapyr, benefin, and acifluorfen.
- the active ingredient can be a pharmaceutical or cosmetic compound such as a non-steroidal anti-inflammatory (e.g., ketoprofen), metronidazole, acetyl salicylic acid, clotrimazole, insulin, lidocaine, hydrochloride, nitroglycerin, prilocaine, tetracycline hydrochloride, benzylpenicillin, acyclovir, guaifenesin, melatonin, metronidazole, phenylpropanolamine, pseudophedrine hydrochloride, timolol maleate, acyclovir, hydrocortisone, minoxidil (Rogaine), sildenafil citrate (Viagra), eflomithine HCl (Vaniqua), zinc pyrithione, a skin moisturizer, and combinations thereof.
- the active ingredient can also be an enzyme or a nutrient such as a vitamin or mineral, such as vitamin E, C, Zinc, or Iron
- FIG. 1 represents a ternary phase diagram 100 of a system of a hydrotrope 103, a combination of an amphiphile an additive 106, and a solvent 109.
- Single phases can be used as a precursor.
- compositions falling in the single phase regions of the phase diagram such as the isotropic liquid region 124 and the lamellar region 121, are suitable precursors.
- Compositions falling in the multiple phase region 112 wherein cubic phase does not form are also suitable as precursors.
- Compositions that do not fall in the Pn3m cubic phase region 115 and the Ia3d cubic phase region 118 are suitable precursors as discussed in Luzzati et al., J. Mol. BioL, 229, 540-551 (1993).
- a precursor can be used in an application where cubic phase formation is desired under a certain set of conditions, for example, the presence of sweat, saliva, or other material that will change the system composition such that it is in the area surrounding either of the two cubic phases 115, 118 or within the two cubic phases 115, 118.
- the precursor of this invention may be used to directly form either bulk cubic gel, dispersed cubic gel particles, or a combination of the two, all depending on the desires of the formulator.
- Bulk Cubic Gel and Dispersions In FIG. 1, dispersions should fall within the region representing cubic liquid crystalline phase in combination with another phase 127 on the phase diagram 100.
- the mass fractions of (A), (B), (C), and (D) in the bulk cubic gel preferably follow the relationship of 0.1 a > 0, 0.8 > b > 0, 0.4 > c > 0, and 0.1 > d > 0, more preferably, 0.1 > a > 0, 0.1 > b > 0, 0.95 > c > 0, and 0.1 > d > 0.
- the amounts of (A), (B), (C), and (D) differ so that either a bulk cubic gel or a cubic liquid crystalline gel dispersion forms.
- the amount of each ingredient should be such that the combined ingredients form a cubic liquid crystalline phase or a cubic liquid crystalline phase in combination with one or more other phases.
- a combination of the amounts of the ingredients that fall within the cubic liquid crystalline region in the phase diagram will be suitable for this invention.
- the amount of solvent 109, hydrotrope 103, and combination of amphiphile and additive 106 should fall in one of the cubic phase regions 115, 118 in the phase diagram.
- an active can be added to the bulk cubic gel.
- a method for the preparation of a precursor comprises 1) combining an amphiphile capable of forming a cubic liquid crystalline phase with an optional hydrotrope, 2) adding an additive selected from the group consisting of an anchor, a tether, and combinations thereof, and 3) optionally adding a solvent.
- step 1) the hydrotrope and amphiphile are combined.
- the hydrotrope and amphiphile can be combined by mixing.
- the amphiphile is a solid, such as monoolein
- the hydrotrope and amphiphile are preferably combined by heating the amphiphile beyond its melting point and then combining the melted amphiphile with hydrotrope.
- the amphiphile can be fragmented into solid particles and combined with hydrotrope.
- the hydrotrope can be dissolved in an aqueous hydrotrope solution, and the solution combined with the amphiphile in step
- Steps 2) and 3) can be carried out any time during the method.
- the product of step 2) can contain amounts of (A), (B), (C), and (D) corresponding to any region on the relevant phase diagram where cubic phase does not form.
- the product of step 3) is an isotropic liquid at 25°C.
- the method may further comprise adding an active at any time as described supra.
- the amount of active can be sufficient when a gel formed from the precursor contains up to about 15 %, preferably from about 0 to about 10 percent wt/wt of the combined weights of (A), (B), (C), and (D).
- Bulk cubic liquid crystalline gel can be prepared by applying a stimulus to the prepared precursor.
- Non-limiting stimuli include temperature changes, pressure changes, addition of a salt, a pH change, addition of a specified material such as additional hydrotrope, amphiphile, or solvent, removal of a specified material such as a portion of the hydrotrope, amphiphile, or solvent, and combinations thereof.
- the precursor can be diluted, for example, by mixing the precursor with additional (A) hydrotrope, (B) amphiphile, or (C) solvent.
- a bulk cubic liquid crystalline gel can be prepared directly by combining amounts of ingredients (A), (B), (C), and (D) corresponding to a cubic phase region on the relevant phase diagram. After formation of the bulk cubic liquid crystalline gel has been completed, all or a portion of the hydrotrope may be removed.
- Dispersed cubic liquid crystalline gel particles can be prepared from bulk cubic gels or directly from at least one precursor.
- a dispersion can be prepared directly from at least one precursor by 1) a dispersing step selected from the group consisting of a) dispersing the precursor described above in a solvent, and b) dispersing solvent in the precursor and thereafter diluting; and 2) optionally stabilizing the product of step 1).
- Steps a) and b) may be performed by applying fluid shear such as in a shear mill, applying ultrasonic waves, extruding through a small pore membrane (membrane emulsification), cross membrane emulsification, impinging a stream of the precursor and a stream of solvent from opposing jets, using a static mixer, or combining streams of solvent and the precursor in a micro-mixer that utilizes either laminar or turbulent shear flow conditions to disperse the streams.
- the precursor may also be contacted with a solvent by spraying a fine mist of the precursor into an environment comprising solvent vapors. A spray allows the formation of droplets with a surface coating of cubic liquid crystalline phase.
- the droplets can then be collected in bulk in water to disperse the particles and complete their conversion to cubic liquid crystalline gel particles.
- solvent can be added to the precursor by bubbling vaporized solvent into the precursor.
- the product of step 1) is a dispersion of cubic liquid crystalline gel particles that can be unstable against aggregation.
- the product of step 1) can be stabilized by adding (F) a stabilizer, or by forming a coating of lamellar liquid crystalline phase on the surfaces of the particles.
- the product of step 1) may also be stabilized by direct dispersion into a viscous aqueous matrix such as a matrix formed by a water-soluble stabilizer such as Carbomer cellulosic polymer.
- the product of step 2) is a dispersion of colloidally stable cubic liquid crystalline gel particles.
- steps 1) and 2) can be combined. Steps 1) and 2) can be combined by adding a stabilizer (F) to a solvent (C) to form a stabilizing composition and thereafter combining the stabilizing composition with the product of step 1).
- the precursor can be diluted to form an intermediate such as a dispersion of lamellar liquid crystalline particles, vesicles, or an easily dispersed emulsion.
- an intermediate such as a dispersion of lamellar liquid crystalline particles, vesicles, or an easily dispersed emulsion.
- Any of these intermediates can be used to form a colloidally stable dispersion of cubic liquid crystalline gel particles by further dilution in combination with any of the above dispersion and stabilization techniques in steps 1) and 2). This is because the dispersions may be formed and stabilized prior to particle formation.
- Cubic gel particles can also be prepared by fragmenting a bulk cubic gel by subjecting the bulk cubic gel to shear in a shear mill, ultrasonication, micromix
- Particles can be isolated from a prepared dispersion by removing a sufficient amount of solvent (C) and/or a combination of solvent (C) and hydrotrope (A).
- the particles may be dried by evaporation or removed from the dispersion by centrifugation, filtration, and combinations thereof.
- FIG. 2 illustrates a negatively charged material 201 (e.g., ionized Ketoprofen) anchored into the bicontinuous cubic liquid crystal 200 functionalized with dioctyldecyl dimethyl amine chloride 202 (DODMAC). This interaction can increase the level of loading and enhances the release profile of the material.
- the precursors, gels, dispersions, and particles can be used for topical delivery of pharmaceutical and/or cosmetic active ingredients such as Ketoprofen and those described above.
- Precursors, gels, dispersions, and particles can be used for nutrient delivery, encapsulation, stabilization, and/or enzyme delivery, and to generate trans-membrane protein crystal structures. Further, cuboplexes can be fabricated into mini-reactors by attaching an enzyme inside the pores that consume some biological targets, and to remove harmful compounds from their environment, such as heavy metals, which would concentrate in the aggregates and then skimmed off waste water.
- Functionalization can offer the added ability to enhance the exterior properties of materials and can help colloidal stability.
- the exterior of the cuboplexes might be modified with a charge to enhance deposition on substrates.
- target substrates include skin, hair, fabric, and plant surfaces. It would also be possible to provide selective adhesion of an aggregate to biological sites by affixing an enzymatic protein to the outside of an aggregate with the aggregate containing some pharmaceutical interest. It is believed that affixing large molecules can act as a steric prevention of coalescence generated by attached polymers.
- Functionalization offers the further ability to create "on demand” products. "On demand” means that the internal and external properties of a cuboplex release or entrap materials as a consequence of a stimulus.
- Non-limiting releases or entrapments may be instigated by pH (charged species with a defined pKa), by the addition of salt (reduce the shielding of electrostatics), by the introduction of dielectric solvents (minimize the role of electrostatics), or by the addition or selective removal of components which can selectively bind to the regions.
- the controlled release delivery of active ingredients, including agrochemicals such as herbicides and pesticides to a substrate such as a plant or insect surface can be performed using the cubic gel precursors by evaporation and/or dilution.
- Evaporation and/or dilution processes produce "responsive" liquids that provide targeted delivery of active ingredients in response to a stimulus, such as dilution by residual moisture or evaporation as a consequence of spraying.
- Evaporation and dilution processes may be represented by a line drawn from a starting point to an ending point on the phase diagram. Dilution The starting point for a dilution process can be any previously described precursor region on the phase diagram and the ending point can be any region of single-phase cubic liquid crystal or multiple-phase.
- the trajectory of a dilution path can be determined by a straight line drawn between the starting point and the solvent apex of a ternary phase diagram. Once the starting point is chosen, the ending point should fall along that straight line.
- a mixture of amphiphile and either an active ingredient with hydrotropic properties or a separate active in combination with a hydrotrope is combined to form an isotropic liquid precursor which is then sprayed onto a substrate coated with solvent.
- Spraying can disperse the precursor into small droplets that coat the substrate and contact the solvent.
- Mixing solvent on the substrate with the precursor initiates dilution driving the droplet system into the cubic plus solvent region of the phase diagram, producing a coating of solvent, active ingredient, and cubic liquid crystalline material that slowly releases active into the substrate.
- Monoglycerides are preferred amphiphiles for plant applications because it is believed that monoglycerides can enhance leaf surface penetration by active ingredients. Evaporation
- the evaporative process can be similar to dilution because the starting point on the ternary phase diagram is also a precursor from which solvent and/or hydrotrope can be evaporated to drive the system to an ending point on the phase diagram in a region of single-phase cubic liquid crystal or multiple-phase (in which at least one phase is cubic liquid crystal).
- choosing a starting point dictates that the process trajectory will progress toward the amphiphile apex of the phase diagram.
- the exact path taken can be a function of the vapor pressure of the mixture of the solvent and the hydrotrope, and may not be linear as in the case of dilution. Evaporation may occur during spraying and/or after deposition onto the target substrate.
- a mixture of amphiphile, hydrotrope, solvent, and active ingredient is combined to form an isotropic liquid precursor which is sprayed onto a substrate.
- Spraying can disperse the precursor into small droplets, increasing the effective spray area and the ability to evaporate solvent and/or hydrotrope.
- the droplet system rapidly passes into the cubic liquid crystalline regions of the ternary phase diagram, producing a coating of solvent, active, and cubic liquid crystalline material that slowly releases the active into the substrate.
- Monoglycerides are preferred amphiphile for plant applications because it is believed that monoglycerides can enhance leaf surface penetration by the active ingredients.
- a compound for use as a hydrotrope is dissolved in water in amounts to form a hydrotrope solution.
- the solution is added to monoolein (DIMODAN® MO90K) to yield a composition.
- the composition is left to equilibrate overnight at a temperature of 25 to 30°C and analyzed by polarized light microscopy (PLM), discussed supra.
- PLM polarized light microscopy
- cryo-TEM Samples are evaluated to determine whether cubic phase formed by cryo-TEM.
- cryo-TEM the samples are prepared in a controlled environment vitrification system (CEVS), described by Bellare, J. R., Davis, H. T., Scriven, L. E., Talmon, Y., "Controlled environment vitrification technique", J Electron Microsc. Tech., 1988, 10, 87-111.
- CEVS controlled environment vitrification system
- SAXS patterns are unique for each type of liquid crystal. Therefore, it is an excellent technique to confirm the structure of the liquid crystals. Exemplary SAXS patterns for liquid crystal phases are given in Luzzati, V., Tardieu, A., Gulik-Kryzwicki,
- Example 4 A mixture of 2 grams monoolein, 4.67 grams pH 10 buffer, 2% sodium stearate and 4% ethanol (a hydrotrope) is prepared and analyzed as in Comparative Example 2.
- Example 4 A mixture of 2 grams monoolein, 4.67 grams pH 10 buffer, 2% sodium stearate and 4% ethanol (a hydrotrope) is prepared and analyzed as in Comparative Example 2.
- Example 4 A mixture of 2 grams monoolein, 4.67 grams pH 10 buffer, 2% sodium stearate and 4% ethanol (a hydrotrope) is prepared and analyzed as in Comparative Example 2.
- Example 4 A mixture of 2 grams monoolein, 4.67 grams pH 10 buffer, 2% sodium stearate and 4% ethanol (a hydrotrope) is prepared and analyzed as in Comparative Example 2.
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- Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Silicates, Zeolites, And Molecular Sieves (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Liquid Crystal Substances (AREA)
Abstract
Description
Claims
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US27030601P | 2001-02-21 | 2001-02-21 | |
US270306P | 2001-02-21 | ||
PCT/US2002/004838 WO2002068561A2 (en) | 2001-02-21 | 2002-02-20 | Cubic liquid crystalline phase precursor |
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EP1373433A1 true EP1373433A1 (en) | 2004-01-02 |
EP1373433B1 EP1373433B1 (en) | 2008-07-23 |
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US (1) | US6656385B2 (en) |
EP (1) | EP1373433B1 (en) |
JP (1) | JP2004526830A (en) |
CN (1) | CN1243079C (en) |
AT (1) | ATE402241T1 (en) |
AU (1) | AU2002242195B2 (en) |
CA (1) | CA2434655C (en) |
DE (1) | DE60227789D1 (en) |
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WO (1) | WO2002068561A2 (en) |
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US20100004124A1 (en) * | 2006-12-05 | 2010-01-07 | David Taft | Systems and methods for delivery of materials for agriculture and aquaculture |
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JP2004526830A (en) | 2004-09-02 |
US6656385B2 (en) | 2003-12-02 |
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ATE402241T1 (en) | 2008-08-15 |
CA2434655A1 (en) | 2002-09-06 |
DE60227789D1 (en) | 2008-09-04 |
CA2434655C (en) | 2007-08-07 |
AU2002242195B2 (en) | 2006-08-03 |
CN1243079C (en) | 2006-02-22 |
US20020158226A1 (en) | 2002-10-31 |
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EP1373433B1 (en) | 2008-07-23 |
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